Warfarin vs Edoxaban

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original article

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 369;15 nejm.org october 10, 20131406

Edoxaban versus Warfarin for the Treatmentof Symptomatic Venous Thromboembolism

The Hokusai-VTE Investigators*

The members of the writing committee(Harry R. Bller, M.D., Herv Dcousus,M.D., Michael A. Grosso, M.D., MicheleMercuri, M.D., Saskia Middeldorp, M.D.,Martin H. Prins, M.D., Gary E. Raskob,

Ph.D., Sebastian M. Schellong, M.D., LeeSchwocho, Ph.D., Annelise Segers, M.D.,Minggao Shi, Ph.D., Peter Verhamme, M.D.,and Phil Wells, M.D.) assume responsibilityfor the content and integrity of the article.Address reprint requests to Dr. Bller atthe Department of Vascular Medicine, Aca-demic Medical Center, F4-275, Meiberg-dreef 9, 1105 AZ Amsterdam, the Nether-lands, or at [email protected].

*The aff iliations of the authors (membersof the writing committee) are listed in theAppendix. The investigators participatingin the Hokusai-VTE study and the studycommittees are listed in the Supplemen-tary Appendix, available at NEJM.org.

This article was published on September 1,2013, and updated on January 2, 2014, atNEJM.org.

N Engl J Med 2013;369:1406-15.

DOI: 10.1056/NEJMoa1306638

Copyright 2013 Massachusetts Medical Society.

A b s t ra c t

Background

Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in

patients with venous thromboembolism is unclear.

Methods

In a randomized, double-blind, noninferiority study, we randomly assigned patientswith acute venous thromboembolism, who had initially received heparin, to receive

edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of

patients with creatinine clearance of 30 to 50 ml per minute or a body weight below

60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months.

The primary efficacy outcome was recurrent symptomatic venous thromboembolism.

The principal safety outcome was major or clinically relevant nonmajor bleeding.

Results

A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pul-

monary embolism. Among patients receiving warfarin, the time in the therapeutic

range was 63.5%. Edoxaban was noninferior to warfarin with respect to the pri-

mary efficacy outcome, which occurred in 130 patients in the edoxaban group

(3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% con-

fidence interval [CI], 0.70 to 1.13; P


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Edoxaba n vs. Warfarin for V enous Thromboembolism

n engl j med 369;15 nejm.org october 10, 2013 1407

Venous thromboembolism is the third

most common cardiovascular disease after

myocardial infarction and stroke, affecting at

least 700,000 persons annually in North America.1-3

The standard treatment consists of low-molecular-

weight heparin followed by vitamin K antagonists.4

A number of studies have established that new

oral anticoagulants with or without initial hepa-rin therapy are effective alternatives.5-8

Edoxaban is a direct inhibitor of activated fac-

tor X with a rapid onset of action. It is admin-

istered orally once daily and has proven anti-

thrombotic efficacy.9-11The Hokusai-VTE study

was a randomized, double-blind clinical trial that

was conducted to evaluate edoxaban for the treat-

ment of venous thromboembolism. The study was

designed with the aim of broadening applicability

to real-world practice and encouraging the enroll-

ment of all patients, including those with exten-

sive disease, by specifying that treatment shouldbe initiated with the proven, global standard of

parenteral heparin; that the dose of the study

drug should be halved in patients perceived to be

at higher risk for bleeding (e.g., those with renal

impairment or low body weight); and that physi-

cians should be allowed to adjust the duration of

treatment after 3 months according to their clini-

cal judgment or in keeping with evolving evidence.

In addition, patients were followed for 12 months

regardless of the duration of therapy to compare

the clinical outcomes of the two study regimens.

Methods

Study Oversight

In this randomized, double-blind trial, we com-

pared heparin (enoxaparin or unfractionated

heparin) followed by edoxaban with heparin fol-

lowed by warfarin with respect to efficacy and

safety in patients with deep-vein thrombosis,

pulmonary embolism, or both.12A coordinating

committee in collaboration with the sponsor

(Daiichi Sankyo) was responsible for the designand oversight of the study and for developing the

protocol. The institutional review board at each

participating center approved the protocol. All

patients provided written informed consent. The

sponsor was responsible for the collection and

maintenance of the data. An independent com-

mittee, whose members were unaware of the

study-group assignments, adjudicated all sus-

pected outcomes and the results of baseline im-

aging tests and assessed the anatomical extent of

thrombosis. An independent data and safety mon-

itoring committee periodically reviewed study out-

comes. The members of the writing committee

wrote all drafts of the manuscript (no one who is

not a named author contributed substantially to

the manuscript), verified the data, and vouch for

the completeness of the data, the accuracy of the

analyses, and the fidelity of the study to the proto-col. The protocol and accompanying documents

are available with the full text of this article at

NEJM.org.

Patients

Patients 18 years of age or older were eligible if

they had objectively diagnosed, acute, symptom-

atic deep-vein thrombosis involving the popliteal,

femoral, or iliac veins or acute, symptomatic pul-

monary embolism (with or without deep-vein

thrombosis). Patients were excluded if they had

contraindications to heparin or warfarin, hadreceived treatment for more than 48 hours with

therapeutic doses of heparin, had received more

than one dose of a vitamin K antagonist, had

cancer for which long-term treatment with low-

molecular-weight heparin was anticipated, had

another indication for warfarin therapy, contin-

ued to receive treatment with aspirin at a dose of

more than 100 mg daily or dual antiplatelet ther-

apy, or had creatinine clearance of less than 30 ml

per minute. The full list of exclusion criteria is pro-

vided in the protocol.

Randomization and Study Treatment

Randomization was performed with the use of

an interactive Web-based system, with stratif ica-

tion according to the qualifying diagnosis (deep-

vein thrombosis or pulmonary embolism), pres-

ence or absence of temporary risk factors, and

the dose of edoxaban. All patients received initial

therapy with open-label enoxaparin or unfrac-

tionated heparin for at least 5 days.12Edoxaban

or warfarin was administered in a double-blind,

double-dummy fashion.Edoxaban (or placebo) was started after dis-

continuation of initial heparin. Edoxaban was ad-

ministered at a dose of 60 mg orally once daily,

taken with or without food, or at a dose of 30 mg

once daily in patients with a creatinine clearance

of 30 to 50 ml per minute or a body weight of

60 kg or less or in patients who were receiving

concomitant treatment with potent P-glycoprotein

inhibitors.

Warfarin (or placebo) was started concurrently

The New England Journal of Medicine

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with the study regimen of heparin, with adjust-

ment of the dose to maintain the international

normalized ratio (INR) between 2.0 and 3.0. All

measurements were performed by means of a

point-of-care device that provided an actual INR

value for patients receiving warfarin and a sham

INR value for patients receiving edoxaban.12INR

measurements were required to be performed atleast monthly.

Treatment with edoxaban or warfarin was to

be continued for at least 3 months in all patients

and for a maximum of 12 months. The duration

was determined by the treating physician on the

basis of the patients clinical features and pa-

tient preference.

Outcome Measures

The primary efficacy outcome was the incidence

of adjudicated symptomatic recurrent venous

thromboembolism, which was defined as a com-posite of deep-vein thrombosis or nonfatal or fa-

tal pulmonary embolism. Death was adjudicated

as related to venous thromboembolism, other

cardiovascular disease, bleeding, or other causes.

Pulmonary embolism was considered to be the

cause of death if there was objective documenta-

tion that a pulmonary embolism caused the death

or if the death could not be attributed to a docu-

mented cause and pulmonary embolism could

not be ruled out. Prespecified secondary efficacy

outcomes included the primary efficacy outcome

combined with either death from cardiovascular

causes or death from any cause.

The principal safety outcome was the inci-

dence of adjudicated clinically relevant bleeding,

which was defined as a composite of major or

clinically relevant nonmajor bleeding. Bleeding

was defined as major if it was overt and was as-

sociated with a decrease in hemoglobin of 2 g

per deciliter or more or required a transfusion of

2 or more units of blood, occurred in a crit ical

site, or contributed to death.13Clinically relevant

nonmajor bleeding was defined as overt bleedingthat did not meet the criteria for major bleeding

but was associated with the need for medical

intervention, contact with a physician, or inter-

ruption of the study drug or with discomfort or

impairment of activities of daily life.14Net clin-

ical benefit was determined on the basis of the

composite of symptomatic recurrent venous

thromboembolism or major bleeding. The criteria

for adjudication of outcomes are provided in the

Supplementary Appendix, available at NEJM.org.

Surveillance and Follow-up

Patients underwent assessment, in the clinic or

by telephone, on days 5 through 12, 30, and 60

after randomization and monthly thereafter while

they were taking the study drug or every 3 months

after discontinuing the study drug. All patients

were to be contacted at month 12. Patients were

instructed to report symptoms suggestive of re-current venous thromboembolism or bleeding.

Appropriate diagnostic testing, laboratory test-

ing, or both were required in patients with sus-

pected events.

Statistical Analysis

The study was designed as an event-driven trial

to test the hypothesis that edoxaban would be

noninferior to warfarin with respect to the pri-

mary efficacy outcome, with an upper limit of

the confidence interval for the hazard ratio of 1.5

and a two-sided alpha level of 0.05. This margincorresponds to retention of at least 70% of the

treatment effect of warfarin.

Assuming equal efficacy of edoxaban and

warfarin, we estimated that 220 events would

need to occur for the study to have 85% power

to show the noninferiority of edoxaban. When

we determined that the targeted number of

events was expected to be accrued, we set the

date for concluding the study (study closure)

such that the last patient who underwent ran-

domization would complete 6 months of study

treatment and follow-up. Assuming a 3% inci-

dence of the primary efficacy outcome, we esti-

mated that we would have to enroll at least 7500

patients.

All efficacy analyses were performed in the

modified intention-to-treat population, which in-

cluded all patients who underwent randomization

and received at least one dose of the study drug.

The primary analysis included all efficacy out-

comes from randomization through the end of

12 months or study closure (overall study period),

regardless of the duration of the patients studytreatment. The time to the first primary efficacy

outcome was analyzed with the use of a Cox

proportional-hazards model with stratification

factors as covariates. In addition, the primary ef-

ficacy outcome was evaluated for the on-treatment

period the time during which the patients

were receiving the study drug or within 3 days

after the study drug was stopped or interrupted.

Analyses of bleeding outcomes included patients

who received at least one dose of the study drug





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(safety population). The time to clinically relevant

bleeding during the on-treatment period was com-

pared with the use of the same Cox proportional-

hazards model that was used for the primary effi-

cacy outcome. Time-to-event curves were calculated

with the use of the KaplanMeier method.

Prespecified subgroup analyses were per-

formed in subgroups defined according to thequalifying diagnosis and according to status

with respect to right ventricular dysfunct ion

(evidence or no evidence) in patients with pul-

monary embolism. The time in the therapeutic

INR range was calculated with the use of stan-

dard methods,15with the initial heparin lead-in

period not included and with correction for

planned interruptions. In all patients with pul-

monary embolism, N-terminal probrain natri-

uretic peptide (NT-proBNP) levels were mea-

sured at baseline (morning sample) in a core

laboratory. Right ventricular dysfunction wasdefined as an NT-proBNP level of 500 pg per

milliliter or higher.16,17In addition, an indepen-

dent reviewer who was unaware of the treatment

assignments evaluated right ventricular dimen-

sions on the qualifying computed tomographic

scan in a random sample of 1002 patients. Right

ventricular dysfunction was defined as the ratio

of right ventricular diameter to left ventricular

diameter of 0.9 or more.18,19

Results

Patients and Treatment

From January 2010 through October 2012, a total

of 8292 patients were enrolled at 439 centers in

37 countries (Fig. 1). The baseline characteristics

of the patients were similar in the two study

groups (Table 1). The median duration of heparintreatment after randomization was 7 days. De-

tails of the actual duration of treatment with the

study drug are provided in Table S2 in the Sup-

plementary Appendix; 40% of patients were

treated for 12 months. Adherence to edoxaban

treatment was 80% or more in 99% of the pa-

tients in that group. Among patients receiving

warfarin, the INR was in the therapeutic range

for 63.5% of the time, above 3.0 for 17.6% of the

time, and below 2.0 for 18.9% of the time.

Recurrent Venous Thromboembolism

A recurrence of venous thromboembolism dur-

ing the overall study period occurred in 130 of

4118 patients (3.2%) in the edoxaban group and

in 146 of 4122 patients (3.5%) in the warfarin

group (hazard ratio with edoxaban, 0.89; 95%

confidence interval [CI], 0.70 to 1.13; P


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course of recurrent venous thromboembolic

events are shown in Table 2 and Figure 2.

The upper limits of the 95% confidence inter-

vals of the hazard ratios for recurrent venous

thromboembolism in patients who presented with

deep-vein thrombosis or pulmonary embolism

did not exceed the prespecified margin of 1.5

(Table 2). Among patients with pulmonary em-

bolism and evidence of right ventricular dysfunc-

tion (NT-proBNP level of 500 pg per milliliter),

Table 1.Demographic and Clinical Characteristics of the Patients.*

Characteristic All PatientsPatients with

Deep-Vein Thrombosis OnlyPatients with

Pulmonary Embolism

Edoxaban(N = 4118)

Warfarin(N = 4122)

Edoxaban(N = 2468)

Warfarin(N = 2453)

Edoxaban(N = 1650)

Warfarin(N = 1669)

Age

Mean yr 55.716.3 55.916.2 54.716.0 54.915.9 57.116.6 57.416.5

75 yr no. (%) 560 (13.6) 544 (13.2) 282 (11.4) 273 (11.1) 278 (16.8) 271 (16.2)

Male sex no. (%) 2360 (57.3) 2356 (57.2) 1497 (60.7) 1481 (60.4) 863 (52.3) 875 (52.4)

Weight no. (%)

60 kg 524 (12.7) 519 (12.6) 320 (13.0) 304 (12.4) 204 (12.4) 215 (12.9)

>100 kg 611 (14.8) 654 (15.9) 360 (14.6) 379 (15.5) 251 (15.2) 275 (16.5)

Creatinine clearance 30 to 50 ml/min no. (%)

268 (6.5) 273 (6.6) 152 (6.2) 153 (6.2) 116 (7.0) 120 (7.2)

Patients receiving 30 mgof edoxaban at randomiza-tion no. (%)

733 (17.8) 719 (17.4) 425 (17.2) 411 (16.8) 308 (18.7) 308 (18.5)

Anatomical extent of qualifying event

no. (%)Limited 603 (24.4) 596 (24.3) 128 (7.8) 123 (7.4)

Intermediate 795 (32.2) 773 (31.5) 679 (41.2) 682 (40.9)

Extensive 1035 (41.9) 1049 (42.8) 743 (45.0) 778 (46.6)

Not assessable 35 (1.4) 35 (1.4) 100 (6.1) 86 (5.2)

Concomitant DVT no. (%) 410 (24.8) 404 (24.2)

Baseline NT-proBNP no. (%)

Patients with measurement 1484 (89.9) 1505 (90.2)

Patients with level 500 pg/ml 454 (27.5) 484 (29.0)

Right ventricular dysfunction no./total no. (%)

172/498 (34.5) 179/504 (35.5)

Causes of DVT or PE no. (%)Unprovoked 2713 (65.9) 2697 (65.4) 1666 (67.5) 1655 (67.5) 1047 (63.5) 1042 (62.4)

Temporary risk factor 1132 (27.5) 1140 (27.7) 655 (26.5) 655 (26.7) 477 (28.9) 485 (29.1)

Cancer 378 (9.2) 393 (9.5) 209 (8.5) 205 (8.4) 169 (10.2) 188 (11.3)

Previous VTE 784 (19.0) 736 (17.9) 416 (16.9) 414 (16.9) 368 (22.3) 322 (19.3)

* Plusminus values are means SD. There were no significant differences between the edoxaban group and the warfarin group in any of thecharacteristics listed here. DVT denotes deep-vein thrombosis, NT-proBNP N-terminal probrain natriuretic peptide, PE pulmonary embo-lism, and VTE venous thromboembolism.

Patients with a body weight below 60 kg or a creatinine clearance of 30 to 50 ml per minute, as well as patients who were receiving concom-itant P-glycoprotein inhibitors such as verapamil or quinidine, received 30 mg instead of 60 mg of edoxaban to maintain similar exposure tothe cohort receiving 60 mg.

Among patients with DVT alone, limited refers to an event in which the most proximal site was the popliteal vein; intermediate, an event inwhich the most proximal site was the superficial femoral vein; and extensive, an event in which the most proximal site was the common

femoral or iliac vein. Among patients with PE, limited refers to involvement of 25% or less of the vasculature of a single lobe; intermediate,involvement of more than 25% of the vasculature of a single lobe or multiple lobes with involvement of 25% or less of the entire vascula-ture; and extensive, involvement of multiple lobes with 25% or more of the entire vasculature.

Right ventricular function was assessed by calculating the ratio of the right ventricular diameter to the left ventricular diameter on a four-chamber view of the qualifying index pulmonary embolism on a computed tomographic scan.

A patient could have multiple risk factors. Temporary risk factors included recent surgery, trauma, immobilization, or use of estrogen.





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Table 2.Clinical Outcomes during Overall Study Period and On-Treatment Period.*

OutcomeEdoxaban(N = 4118)

Warfarin(N = 4122)

Hazard Ratio withEdoxaban (95% CI) P Value

Primary efficacy outcome: first recurrent VTE orVTE-related death no./total no. (%)

All patients

Event during overall study period 130/4118 (3.2) 146/4122 (3.5) 0.89 (0.701.13)


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recurrent venous thromboembolism occurred in

15 of 454 patients (3.3%) in the edoxaban group

and in 30 of 484 patients (6.2%) in the warfarin

group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98).

Similar results were observed among patients

with right ventricular dysfunction as assessed by

means of computed tomography (hazard ratio,

0.42; 95% CI, 0.15 to 1.20).

Among patients who qualified for the 30-mg

dose of edoxaban, recurrent venous thrombo-

embolism occurred in 22 of 733 patients (3.0%)

receiving edoxaban, as compared with 30 of the

719 patients (4.2%) receiving warfarin (hazard

ratio, 0.73; 95% CI, 0.42 to 1.26). The hazard

ratios for recurrent venous thromboembolism in

the other prespecified subgroups are shown in

Figure S1 in the Supplementary Appendix.

Bleeding Outcomes

Clinically relevant bleeding (major or nonmajor)

occurred in 349 of 4118 patients (8.5%) in the

edoxaban group and in 423 of 4122 patients

(10.3%) in the warfarin group (hazard ratio, 0.81;

95% CI, 0.71 to 0.94; P = 0.004 for superiority).

The difference in risk (edoxaban minus warfarin)

was 1.8 percentage points (95% CI, 3.04 to

0.53). Major bleeding occurred in 56 patients

(1.4%) in the edoxaban group and in 66 patients

(1.6%) in the warfarin group (hazard ratio, 0.84;

95% CI, 0.59 to 1.21). The clinical presentation

and time course of bleeding events are provided

in Table 2 and Figure 3.

Among patients who qualified for the 30-mg

dose of edoxaban, clinically relevant bleeding

occurred in 58 of 733 patients (7.9%) who re-

ceived edoxaban, and in 92 of the 719 patients

(12.8%) who received warfarin (hazard ratio,

0.62; 95% CI, 0.44 to 0.86). Major bleeding oc-

curred in 11 patients (1.5%) in the edoxaban

group and in 22 patients (3.1%) in the warfarin

group (hazard ratio, 0.50; 95% CI, 0.24 to 1.03).

The hazard ratios for bleeding in the other

prespecified subgroups are provided in Figure S2

in the Supplementary Appendix.

Deaths and Other Adverse Events

The number and causes of death, as well as results

with respect to the net clinical benefit, are shown

in Table S3 in the Supplementary Appendix.

There were 21 acute coronary events in the edox-

aban group (0.5%) and 16 in the warfarin group

(0.4%). The rates of other adverse outcomes were

also similar in the two groups. (Table 2, and Ta-

ble S3 in the Supplementary Appendix).

AdjudicatedRecurrentVTE(%)

100

80

90

70

60

40

30

10

50

20

0

0 30 60 90 120 330 360

Days

No. at RiskEdoxaban

Warfarin

4118

4112

2918

2936

4050

4055

4024

4023

4002

4001

3985

3992

3974

3975

3959

3962

3885

3864

3692

3683

3524

3519

3358

3367

3190

3184

150 180 210 240 270 300

4.0

3.0

2.5

1.5

1.0

0.5

3.5

2.0

0.0

0 30 60 90 120 330 360150 180 210 240 270 300

Edoxaban

Warfarin

Figure 2.KaplanMeier Cumulative Event Rates for the Primary Efficacy Outcome.KaplanMeier curves are shown for the first occurrence of the primary efficacy outcome of adjudicated symptomat-

ic recurrent venous thromboembolism (VTE) a composite of deep-vein thrombosis or nonfatal or fatal pulmo-nary embolism in the overall study period. The inset shows the same data on an enlarged y axis.





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Discussion

In this large, double-blind study involving pa-

tients with venous thromboembolism, treatment

with heparin followed by oral edoxaban once

daily, as compared with standard therapy, was

noninferior with respect to efficacy and superior

with respect to bleeding. We succeeded in enroll-

ing patients across a broad spectrum of venous

thromboembolic manifestations, ranging from

limited proximal deep-vein thrombosis to severe

pulmonary embolism, and the relative efficacy

was observed throughout. In analyses of safety,

the results were consistent with respect to both

major bleeding and clinically relevant nonmajor

bleeding, with fewer fatal and intracranial bleeds

in the edoxaban group (Table 2), although the

between-group difference with respect to major

bleeding did not reach statistical signif icance.Efficacy was evaluated at 12 months of fol-

low-up, regardless of the duration of treatment

a study design that was different from that of

earlier studies.5-8The design of the Hokusai-VTE

study, as compared with a design calling for on-

treatment analyses only, allowed for a better

understanding of the outcomes that may be ex-

pected in clinical practice. In the on-treatment

analysis, we observed low rates of recurrence

that were similar to those seen in contemporary

studies.5-8 In our study, the relative efficacy of

edoxaban was not limited to patients receiving

medication, but it was evident even among those

who stopped treatment before 12 months (Fig. 2).

Some aspects of our trial warrant comment.

Three recent studies focused on a single-drug

approach for all treatment phases.6-8Thus, the

use of the traditional sequence of a heparin lead-

in followed by an oral agent may be considered

a limitation of the Hokusai-VTE study. However,

given the global acceptance of, and confidence in,

initial parenteral treatment, the heparin lead-in

encouraged investigators to enroll a high propor-

tion of patients with severe grades of venous

thromboembolism. When designing the study, we

anticipated that a considerable proportion of pa-

tients with right ventricular dysfunction due to

pulmonary embolism would be included. Wemeasured NT-proBNP levels in all patients with

pulmonary embolism and assessed right ven-

tricular dimensions by means of computed to-

mography in a random subgroup of 1002 of

these patients. Approximately one third had

right ventricular dysfunction. There was a reduc-

tion in recurrences among patients with elevated

NT-proBNP levels in the edoxaban group, and

this finding was supported by the analysis of

AdjudicatedMajoror

ClinicallyRelevant

NonmajorBl

eeding(%)

100

80

90

70

60

40

30

10

50

20

00 30 60 90 120 330 360

Days

No. at RiskEdoxabanWarfarin

41184122

12411212

38403757

36953627

35873522

33823313

33083218

30382979

21922165

20432007

19041883

17641754

16501613

150 180 210 240 270 300

14

10

8

4

2

12

6

00 30 60 90 120 330 360150 180 210 240 270 300

Edoxaban

Warfarin

Figure 3.KaplanMeier Cumulative Event Rates for the Principal Safety Outcome.The principal safety outcome was the incidence of adjudicated clinically relevant bleeding, which was defined as acomposite of major or clinically relevant nonmajor bleeding. The inset shows the same data on an enlarged y axis.





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patients with right ventricular dysfunction as

assessed by means of computed tomography.

The study design aimed to address concerns

that new oral anticoagulants may confer a higher

risk of bleeding among patients with renal im-

pairment and low body weight.12We identified

approximately one fifth of patients with these

risk factors. Halving of the daily dose of edoxa-ban to 30 mg maintained efficacy with signifi-

cantly less bleeding than that observed in the

warfarin group.

To ensure best practice with the comparator,

the quality of warfarin therapy was proactively

monitored throughout the study. This resulted in

an overall time in the therapeutic range of

63.5%, which is a higher percentage of time in

the therapeutic range than the 40 to 50% seen

in registries of clinical practice.20-22 Our find-

ings are likely to be generalizable. In this global

study, we included patients with both provokedand unprovoked venous thromboembolism, and

treatment durations varied from 3 to 12 months

at the discretion of the treating physician. Loss

to follow-up was very low (


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dynamically stable pulmonary embolism:a systematic review. Eur Heart J 2008;29:

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Shepherd Hut in the Pyrenees, Spain Avital Hershkovitz, M.D.



Warfarin vs Edoxaban

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